Abstract 1780: Functional inhibition of RNA-binding protein HuR reverses chemotherapeutic resistance in triple-negative breast cancer
Authors: Lanjing Wei, Qi Zhang, Cuncong Zhong, Jeffrey Aubé, Danny R. Welch, Xiaoqing Wu, Liang Xu
Journal: Cancer Research (2022)

Abstract The 5-year relative survival rate of patients with triple-negative breast cancer (TNBC) is lower than the overall patients with breast cancer. The primary systemic treatment for TNBC remains to be chemotherapy. But chemoresistance frequently develops with the conventional usage of chemotherapy drugs, which results in poorer prognosis and higher recurrence of TNBC than other subtypes of breast cancer. Therefore, to improve the treatment for TNBC, overcoming chemoresistance is a critical challenge to conquer. The RNA-binding protein Hu antigen R (HuR) is a posttranscriptional regulator. It can stabilize target mRNAs through binding to U- or AU- rich elements mainly in 3’ untranslated region (UTR) of mRNA and upregulate their translation level in most cases. The encoded proteins of HuR target mRNAs are implicated in multiple cancer hallmarks, including chemotherapeutic sensitivity. The cytoplasmic accumulation of HuR is reported to contribute to chemoresistance in multiple cancer cells, and HuR inhibition sensitizes cancer cells to chemodrugs. We hypothesize that inhibition of HuR function by disrupting its interaction with mRNA can accelerate the decay of target mRNAs and thus reduce the translation level of proteins responsible for chemoresistance. Recently, our lab identified a small molecule HuR inhibitor, KH-3, which potently inhibits HuR function by disrupting HuR-mRNA interactions. In this study, KH-3 is used as a tool compound to investigate the roles HuR plays in chemoresistance development and evaluate whether HuR inhibition can enhance the efficacy of chemotherapy for TNBC cells. Two MDA-MB-231 cell sublines resistant to docetaxel (231-TR) or doxorubicin (231-DR) were generated in our lab. Compared to the parental cell line, two sub-lines exhibit similar sensitivity to KH-3, and KH-3 re-sensitizes chemoresistant cells to docetaxel or doxorubicin in the MTT-based cytotoxicity assay and the colony formation assay, indicating that HuR inhibition can overcome the acquired chemoresistance. The in vivo efficacy studies in orthotopic xenograft mouse models of human TNBC confirm that KH-3 synergizes docetaxel treatment. Regarding to mechanisms of action, several HuR direct target mRNAs implicated in chemoresistance were found upregulated in the resistant cells, which were reversed by KH-3 treatment. Detailed molecular mechanisms are now under investigation. This study suggests that HuR inhibition is a promising strategy to overcome the challenge of chemoresistance of TNBC. Citation Format: Lanjing Wei, Qi Zhang, Cuncong Zhong, Jeffrey Aubé, Danny R. Welch, Xiaoqing Wu, Liang Xu. Functional inhibition of RNA-binding protein HuR reverses chemotherapeutic resistance in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1780.